Enantioselective Total Synthesis of the Osteoclastogenesis Inhibitor (+)-Symbioimine

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114188062/ABSTRACT

From Prof. Regan J. Thomson's group at Northwestern University, Evanston, IL

A short synthesis of (+)-Symbioimine (1) was recently reported in ACIEE EarlyView. The synthesis an unusual intramolecular Diels-Alder reaction of conjugated cyclic iminium ion intermediate. Compound 1 is believed to find potential uses in preventative treatment of osteroporosis and possibly as an anti-inflammatory therapeutic agent.

In their retro, it was thought that the allylic methyl group in 3 would impose a poor facial selectivity for an exo [4+2] cycloaddition; not enough to drive the reaction to the desired stereochemistry. However, the cyclic iminium species 4 with its stereo-defined allylic methyl group was believed to impose a stronger preference for an endo cycloaddition to provide cycloadducut 5 with good desired stereochemistry. This cycloadduct then could undergo an epimerization to adjust its stereochemistry to an all trans ring junction of 1.

Diene 13 was identified as the needed Diels-Alder precursor and the synthetic route was devised as shown in the scheme below.

Starting from aldehyde 6, HWE olefination proceeded with good yield to provide 7 with excellent E/Z selectivity (>11:1). Conversion to methyl ketone 8 could be performed through Weinreb amide in one step for a small scale or a two-step protocol is necessary for a larger scale synthesis. Mukaiyama aldol of enol ether 9 with acetal 11, followed by the Staudinger-aza-Wittig reaction sequence then provided the key compound 13 in excellent yield.

Heating 13 with TFA effected the formation of 14 followed by cycloaddition-epimerization allowed a rapid access to the imine 16. Treatment of 16 with TFAA then afforded 17 in good overall yield as a single diastereomer. The structure of 17 was characterized with nOe experiments, and could be converted back to 16 under mild reaction conditions by treatment with K2CO3/MeOH.

Treatment of 16 with BBr3 (global demethylation), followed by selective sulfation finally afforded the natural product 1. This synthesis has showcased the use of the dihydropyridinium species (14) in a rare Diels-Alder reaction, which could find more uses in the future. The lower yield of the cycloaddition was probably due to the generation of other unavoidable pyridine derivatives. However, this Diels-Alder reaction may provide a direct support in the biosynthesis of 1. Overall, this is a very nice and short synthesis that could provide rapid access to 1 and its analogs.